Download The effects of normal aging on myelin and nerve fibers: A review

Journal of Neurocytology 31, 581–593 (2002)
The effects of normal aging on myelin and nerve
fibers: A review∗
ALAN PETERS
Department of Anatomy and Neurobiology, Boston University School of Medicine, 715, Albany Street, Boston, MA 02118, USA
[email protected]
Received 7 January 2003; revised 4 March 2003; accepted 5 March 2003
Abstract
It was believed that the cause of the cognitive decline exhibited by human and non-human primates during normal aging was
a loss of cortical neurons. It is now known that significant numbers of cortical neurons are not lost and other bases for the
cognitive decline have been sought. One contributing factor may be changes in nerve fibers. With age some myelin sheaths
exhibit degenerative changes, such as the formation of splits containing electron dense cytoplasm, and the formation on myelin
balloons. It is suggested that such degenerative changes lead to cognitive decline because they cause changes in conduction
velocity, resulting in a disruption of the normal timing in neuronal circuits. Yet as degeneration occurs, other changes, such as
the formation of redundant myelin and increasing thickness suggest of sheaths, suggest some myelin formation is continuing
during aging. Another indication of this is that oligodendrocytes increase in number with age.
In addition to the myelin changes, stereological studies have shown a loss of nerve fibers from the white matter of the cerebral
hemispheres of humans, while other studies have shown a loss of nerve fibers from the optic nerves and anterior commissure
in monkeys. It is likely that such nerve fiber loss also contributes to cognitive decline, because of the consequent decrease in
connections between neurons.
Degeneration of myelin itself does not seem to result in microglial cells undertaking phagocytosis. These cells are probably
only activated when large numbers of nerve fibers are lost, as can occur in the optic nerve.
A reminiscence
When I was asked to contribute an article to this issue of Journal of Neurocytology, dedicated to Sandy
Palay, I considered a number of possible topics and in
the end decided to write about my recent studies of the
effects of age on myelin sheaths. In a sense, this completes a circle, because I first met Sandy in 1960 in Delft
when we were both at the European Regional Conference in Electron Microscopy: he talked about the neurosecretory cells in the preoptic nucleus of fishes and I
gave a paper on the structure of myelin sheaths in the
central nervous system. We met again the following
year in London at the 1961 meeting of the Anatomical
Society of Great Britain and Ireland, and I persuaded
Sandy to come to Edinburgh in 1962 to give the Ramsey
Henderson Trust Lectures. This was the beginning of
a long friendship and a productive scientific association that culminated in the two of us collaborating
with Harry Webster to write “The Fine Structure of the
Nervous System’’, which was first published in 1970.
This atlas with text ran into three editions, and is probably one of the most quoted books in neuroanatomy.
∗ Grant
Since my association with Sandy had its beginnings in
the structure of myelin, it seems appropriate for me to
now return to that topic. Forty years ago, my interest
was in the formation and structure of central myelin:
now it is the other end of spectrum, how myelin sheaths
react to aging and how their structure alters.
Introduction
The majority of studies on the effects of aging on the
nervous system have focused on the changes that occur
as a consequence of Alzheimer’s disease. This is understandable because the effects of this disease are devastating to both patients and their families, but because
of this focus, the effects of normal aging on the nervous
system received little attention and studies only began
to appear frequently some 25 years ago. And yet as human longevity increases and brings about an increase
in the number of citizens that are elderly, we need to
understand what is happening to the brain during normal aging, and what underlies the cognitive declines
sponsor: N.I.H. National Institute on Aging. Grant 1PO AG 00001.
0300–4864
C
2003 Kluwer Academic Publishers
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often associated with normal aging. Many older people show a decline in short term memory; increase in
forgetfulness; increase in the time it takes to learn new
information; and a slowing of the speed of response
to challenging situations. Unfortunately, these cognitive changes can often affect the ability of older people to lead independent lives, and it is only by understanding what is happening in the aging nervous
system that any possible alleviations can be proposed.
Another reason for needing to know what is happening to the normally aging brain is that pathological
changes, such as those occurring in Alzheimer’s disease, can appear late in life, and are superimposed
upon a background of the normal aging changes that
have preceded them. Consequently it is important to
know what types of changes are produced by normal
aging and how they differ from the ones that are disease
related.
The effects of normal aging on numbers
of cortical neurons
Studying the effects of normal aging on the human
brain and correlating any alterations with declines in
cognition presents problems. Delays in obtaining human tissue for examination after death result in deterioration of cells and their components, making it difficult
to carry out useful morphological studies. In addition
it is rare that the cognitive status of an individual has
been accurately recorded before death. These factors
undoubtedly played a role in the development of the
popular concept that the cognitive decline associated
with normal aging is brought about by a significant
loss of cortical neurons.
In the first studies of the effects of age on the human cortex Brody (1955, 1970) concluded that as many
as 50% of neurons are lost with age. Other investigators concurred with this conclusion (see Peters et al.,
1998), and it was not until the 1980s that Haug and
Terry and their colleagues produced contrary evidence.
Thus, Haug and his colleagues (Haug, 1984, 1985;
Haug et al., 1984) showed that many of the early reports of loss of cortical neurons with age could be
attributed to the fact that upon fixation the brains
of younger individuals shrink more than those of
older ones, which have more myelin. Consequently,
when sections of cortical tissue are examined, the
young brains show higher neuronal packing densities
than those of older individuals. After making corrections for this differential shrinkage, Haug and his colleagues concluded there is no significant loss of neurons from the human cerebral cortex with age. Terry
et al. (1987) reached a similar conclusion and suggested that much of the neuronal loss recorded in earlier studies could be attributed to brains of some individuals with undiagnosed Alzheimer’s disease being
included among the older brains that were being eval-
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uated and considered to be normal. In Alzheimer’s disease there is a significant neuronal loss from cerebral
cortex.
In recent studies of the effects of normal human aging more attention has been paid to the selection of the
material being studied and to the way in which neurons are counted, and it is now generally agreed that
although there might be a slight loss of cortical neurons during normal aging, it is nowhere as extensive as
early reports would suggest (see Morrison & Hof, 1997;
Peters et al., 1998).
Because of the problems in obtaining adequately
preserved human material some investigators have
turned to non-human primates, such as the rhesus
monkey, to study normal aging. The advantages of
using non-human primates are that they have a life
span of only 35 years (Tigges et al., 1988), as opposed
to the human life span of 75 to 90 years; they show
cognitive deficits similar to those of humans; and they
do not develop Alzheimer’s disease. Furthermore,
the cognitive status of the monkeys can be assessed
by psychological tests adapted from those used on
humans (e.g., Bachevalier et al., 1991; Albert & Moss,
1996; Herndon et al., 1997) and brain tissue can be
optimally preserved for morphological studies, so that
useful correlations can be made between cognitive
status and alterations in structure.
Interestingly, the first studies of the effects of age on
the monkey brain also led to the conclusion that cortical neurons are lost with age (Brizzee, 1973; Brizzee
et al., 1975), but as with the human studies, more recent
studies of the non-human primate cortex (summarized
in Peters et al., 1998) have concluded that there is no
significant loss of cortical neurons with age from these
non-human primates. This conclusion has led investigators to seek alternative explanations for the cognitive
decline and to examine other components of the central
nervous system. In our case, we have begun to focus on
the effects of age on the myelinated nerve fibers in the
cerebral hemispheres.
The formation of myelin
The myelin sheaths in the central nervous system are
produced by oligodendrocytes. During development,
processes of oligodendrocytes enclose lengths of axons that are to be myelinated, and the outer faces of
the trilaminar plasma membrane of the enclosing process come together to form a mesaxon. Subsequently
the oligodendrocyte process elongates to form a spiral
wrapping around the enclosed axon. In this wrapping
the outer faces of the trilaminar plasma membrane
in successive turns of the spiraling oligodendrocyte
process come together to form what will be the intraperiod or intermediate line of the mature sheath. Eventually cytoplasm is eliminated from the spiraling oligodendrocyte process so that the cytoplasmic faces of the
Myelin and nerve fibers in aging
trilaminar membrane also become apposed. This leads
to the formation of the major dense line and to compact
myelin sheaths (e.g., Peters, 1960, 1964).
The effects of aging on myelin sheaths
In our initial studies of the effects of aging on nerve
fibers we chose to examine the nerve fibers within cerebral cortex (Peters et al., 2000; Peters & Sethares, 2002), in
which the myelin sheaths are usually much better preserved than those in white matter (Figs. 1 and 2). The
reason is that the blood supply to white matter is relatively poor, so that obtaining good fixation of its myelin
sheaths by perfusion fixation is always a problem, and
in our initial studies it was important to differentiate
structural changes that might occur as a result of poor
fixation from those produced as a consequence of aging. In well-preserved cortical tissue the myelin around
nerve fibers is generally compact, although some localized shearing defects may be encountered (Fig. 2).
These shearing defects are fixation artifacts, because
they occur in material from both young and old monkeys, and their frequency increases as the quality of
preservation of tissue decreases. Where the shearing
defects occur the myelin lamellae separate to produce
a bulge (see Peters et al., 2000).
Having established that shearing defects are due to
poor fixation, and not to aging, we were able to extend our studies of the effects of aging to the myelin
sheaths and nerve fibers in cerebral cortex (Peters
et al., 2000; Peters & Sethares, 2002); in corpus callosum (Peters & Sethares, 2002); in optic nerve (Sandell
& Peters, 2001); in anterior commissure (Sandell &
Peters, unpublished); and in the optic radiation. While
shearing defects occur in each of these structures,
and more commonly in white than in gray matter,
there are other alterations in myelin that are agerelated. Such alterations have been encountered in
each of these structures, which suggests that they are
ubiquitous.
Sheaths with dense cytoplasm
The most common age-related defect is one in which
myelin lamellae split at the major dense line to enclose dense cytoplasm (Figs. 1, 2, and 4). The amount
of dense cytoplasm varies, and it may contain inclusions, lysosomes, and vacuoles. When the amount of
dense cytoplasm is small it produces only a minor splitting, but in extreme cases the dense cytoplasm can be
voluminous and occupy splits within several adjacent
portions of the turns of the spiralling lamellae (Fig. 2).
Since the dense cytoplasm is contained within splits
of the major dense line, which is produced by apposition of the cytoplasmic faces of the oligodendroglial
plasma membrane forming the myelin, it must be derived from the parent oligodendrocyte. It is presumed
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that the presence of the dense cytoplasm within a sheath
is an indication that it is degenerating, since Cuprizone
toxicity leads to the formation of dense cytoplasm in
the inner tongue processes of degenerating sheaths
(Ludwin, 1978, 1995), and similar dense cytoplasm occurs in the sheaths of mice with a myelin-associated
glycoprotein (MAG) deficiency (e.g. Lassmann et al.,
1997).
Myelin balloons
A second type of age-related change in myelin sheaths
is the formation of “balloons’’ (Feldman & Peters, 1998).
In light microscopic preparations these balloons appear as holes, but electron microscopy reveals that they
are round, and often spherical, cavities that cause the
myelin sheaths to bulge out (Figs. 1–3). Small balloons
are only a micron or so in diameter, while at the other
extreme are balloons that can achieve diameters of ten
or more microns. Some of the small balloons are produced by cavitation of the cytoplasm on the inside of
the myelin sheath (Fig. 2), but the larger ones are fluid
filled spheres, the fluid being contained in a balloon
produced by a splitting of the intraperiod line of the
compact myelin on one side of the nerve fiber. In favorable transverse sections through affected nerve fibers
the axon can be seen flattened against one side of the
fluid filled balloon (Fig. 3). However, sometimes the
axon is not visible in sections through large balloons,
and it is presumed that such images are produced by
sections that pass in a plane parallel to, and to one side
of, the nerve fiber. Obviously the formation of large balloons must entail the insertion of a significant amount
of new myelin membrane into an existing sheath by the
parent oligodendrocyte.
Balloons have also been described in the cochlear nucleus of the aging gerbil (Faddis & McGinn, 1997), and
it is presumed that the ballooning of myelin sheaths
is a degenerative change, since similar balloons can be
produced experimentally. For example, ballooning of
myelin occurs in severe diabetes (Tamura & Parry, 1994)
and in early phases of Wallerian degeneration in the
dorsal funiculus of the spinal cord when myelin breaks
down as a consequence of dorsal rhizotomy (Franson
& Ronnevi, 1989). Similar balloons are formed in experimental toxicity produced by triethyl tin (e.g., Hirano,
1969; Malamud & Hirano, 1973); by chronic copper poisoning (Hull & Blakemore, 1974); by Cuprizone poisoning (Ludwin , 1978); and by lysolecithin (Blakemore,
1978). In addition, balloons occur in genetically engineered mice that have either a deficit or an excess of
proteolipid protein (Monuki & Lemke, 1995; Anderson
et al., 1998), and in mutant mice that lack galactolipids
(Coetzee et al., 1996, 1998).
The conditions leading to the inclusion of dense
oligodendrocytic cytoplasm within myelin sheaths and
to the formation of balloons suggest that they are both
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Myelin and nerve fibers in aging
degenerative, age-related alterations that affect the integrity of myelin sheaths. It should be pointed out however, that both of these changes are localized and do not
extend along the entire length of an internode. This can
be seen in longitudinal sections of affected nerve fibers
(Fig. 4), and several of these loci of degeneration may
occur along the same internode.
Continued myelin production: Split sheaths
and redundant myelin
Two other age-related changes in myelin sheaths are the
increase in the frequency of appearance of sheaths with
redundant myelin (Fig. 2) and the formation of circumferential splits in thick sheaths (Fig. 3). These alterations
appear to be due to the continued formation of myelin
with age. That myelin production continues with age is
evident when the average thickness of myelin sheaths
in layer 4 of monkey visual cortex is compared in young
(4 to 9 years old) and old (over 24 year of age) monkeys (Peters et al., 2001). The mean number of lamellae
in the sheaths from the young monkeys is 5.6 and in
old monkeys it is 7.0. Much of this increase in mean
thickness is due to the increased frequency in old monkeys of sheaths with more than 10 lamellae. It is these
thicker sheaths that show circumferential splitting, often giving the impression that they are composed of
two separate sets of compact lamellae.
Sheaths of redundant myelin were first described by
Rosenbluth (1966) and Sturrock (1976) found them to
be more common in the white matter of old than young
mice. In transverse sections of these nerve fibers the
sheath of compact myelin is much too large for the enclosed axon, so that the axon is located at one end of
a large loop of myelin (Fig. 2). It seems reasonable to
suggest that the formation of sheaths with redundant
myelin is due to a continued, perhaps uncontrolled,
production of myelin with age.
Altered myelin sheaths and conduction velocity
When the frequency of occurrence of these age-related
changes in myelin are quantified in monkeys it is evident that there is a significant correlation between increasing frequency and increasing age. The frequency
of occurrence of alterations in myelin sheaths in primary visual cortex (Peters et al., 2000) and in area 46 of
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prefrontal cortex (Peters & Sethares, 2002) also correlate significantly with the decline in cognitive behavior
that occurs with increasing age in monkeys (e.g. Moss
et al., 1999). It is suggested that the reason for this correlation between myelin sheath alterations and decline in
cognition is because damage to myelin sheaths results
in a decrease in conduction velocity along nerve fibers.
For example, Xi et al. (1999) found that compared with
young cats the conduction velocity along nerve fibers
in the pyramidal tracts of old cats is decreased by 43%,
and Morales et al. (1987) have also shown that there is a
decrease in conduction velocity of lumbar spinal neurons in old cats. Aston-Jones et al. (1985) have shown
that compared to normal adults there is a 31% lengthening of conduction latencies from nucleus basalis to
frontal cortex in old rats. Also in proteolipid protein
(PLP) deficient mice, in which the myelin is loose or
decompacted (Gutiérrez et al., 1995) conduction velocity is reduced, as it is in nerve fibers that have lost one
or more myelin internodes due to the effects of multiple sclerosis (e.g., Waxman et al., 1995; Felts et al., 1997).
Consequently, there is strong evidence that age and loss
of myelin integrity reduces conduction velocity along
nerve fibers, and it is suggested that the age-related
alterations in the structure of myelin reduce conduction velocity. The result would be to cause a disruption
in the timing of sequential events in neuronal circuits,
and could lead to slowing of responses and difficulty
in recalling information, as occurs in older individuals.
The effects of age on oligodendrocytes
From the above it is apparent that the effects of age on
myelin are complex, because even though some myelin
sheaths are degenerating, there is a concomitant continued production of myelin. This raises the question of
whether there are changes in the myelin-forming oligodendrocytes during normal aging.
When oligodendrocytes in the cerebral cortices of
young and old monkeys are compared (Peters, 1996), it
is seen that with age these cells accumulate increasing
numbers of dense inclusions in their perikarya and that
their processes develop swellings, which also contain
dense inclusions (Figs. 5 and 6). The source of the material in these dense inclusions is not known, but since the
inclusions are not bound by membrane, it is unlikely
that they are derived from phagocytosis. More likely
Fig. 1. Tangential section through layer 4C of the visual cortex of a 32 years old rhesus monkey. One of the nerve fibers (N1 ) has
a split myelin sheath, which contains dark cytoplasm (asterisk) with various inclusions. Another nerve fiber (N2 ) has a sheath
that has split to accommodate a small fluid filled balloon (b.) Scale bar = 1 µm.
Fig. 2. Tangential section through layer 4C of the visual cortex of a 29 year old rhesus monkey. One nerve fiber (N1 ) has a sheath
with several splits that contain dark cytoplasm (asterisk), while another nerve fiber (N2 ) has a small balloon (b). Also contained
in the field is a nerve fiber (N3 ) with redundant myelin. Note the shearing defects in some of the sheaths (arrows). Scale bar =
1 µm.
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Myelin and nerve fibers in aging
the dense material is related to the activity of the oligodendrocytes, although in tissue sections labeled with
antibodies to myelin basic protein no label was found
to be present over the inclusions (Peters & Sethares,
2003).
One obvious question is whether the oligodendrocytes with dense inclusions are connected to sheaths
that are degenerating and have dense material within
them. This is not known because of the inherent difficulty in the mature brain of tracing connections between the myelin sheaths and their parent cells. One
clue that the dense material might originate from degenerating sheaths comes from the study by LeVine and
Torres (1992), who studied the twitcher mouse, which
provides a model for globoid cell leukodystrophy. They
found that the processes of some of the oligodendrocytes in these animals have large swellings adjacent to
their myelin sheaths, while in others the swellings occur
along the lengths of their processes. Their observations
led LeVine and Torres (1992) to suggest that material in
these swellings comes from turnover of material in the
sheaths and that the material moves from the sheath,
along the processes, to their cell bodies. If this is so,
the dense inclusions in the oligodendritic processes and
cell bodies are probably derived from the breakdown
of some of the myelin sheaths. To assess this possibility
it would be useful to determine the composition of the
dense inclusions.
The fact that some myelin sheaths are degenerating with age would suggest that the parent oligodendrocytes are not able to maintain their sheaths and
there may be a number of reasons for this, because
oligodendrocytes are particularly susceptible to damage by a number of substances. For example they
can be adversely affected by complement produced
by macrophages; by cytokines; by nitric oxide; by
changes in intracellular calcium and glutamate levels (e.g. Ludwin, 1997); and by oxidative stress (e.g.,
Juurlink et al., 1998.). However, apart from the dense inclusions that occur in their cytoplasm, no structural alterations have been seen in the oligodendrocytes in our
preparations, and only one or two profiles that might
be dying oligodendrocytes have been encountered.
On the other hand there is some evidence that in cerebral cortex the numbers of oligodendrocytes increases
with age (Peters et al., 1991), and this is supported by the
fact that while oligodendrocytes usually occur singly
in young monkeys, in the cortices of old monkeys it is
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common to see oligodendrocytes in groups and rows
(Fig. 6), which have probably been produced by cell
division (Peters, 1996).
It might be suggested that additional oligodendrocytes are required to remyelinate axons with lengths
that have been left bare as a result of degeneration of
some of their internodes. But it is unlikely that additional cells are derived from mature oligodendrocytes
attached to myelin sheaths (e.g. Ludwin & Bakker, 1988;
Norton, 1996). More likely they are derived from oligodendroglial progenitor cells that are present in the mature central nervous system (e.g., Levine et al., 2001)
and can be labeled with antibodies such as those to the
NG2 proteoglycan and to the platelet derived growth
factor receptor α (PDGFα receptor). It is known that
gliogenesis does not cease in the mature mammalian
central nervous system, and while both astrocytes and
oligodendrocytes appear to be produced from the progenitor cells initially, with increasing age oligodendrocytes are preferentially generated (Levison et al., 1999;
Parnavelas, 1999). This generation of new oligodendrocytes is of great interest because of the potential of these
cells to remyelinated axons following demyelinating lesions, such as those that occur after injury or in multiple sclerosis (e.g., Carroll & Jennings, 1994; Carroll et al.,
1998; Levison et al., 1999; Jones et al., 2002).
Loss of nerve fibers
In cerebral cortex Lintl and Braak (1983) observed that
the intensity of staining of nerve fibers in the stripe of
Gennari in the human cortex decreases with age and
they suggested that this is due to a loss of nerve fibers.
However, in the primary visual cortex of the monkey, even though there is evidence for a breakdown
of myelin, there is no evidence of a significant loss of
nerve fibers with age (Nielsen & Peters, 2000). Nevertheless, there is probably some small loss of nerve fibers
from cerebral cortex with age because a few profiles
of nerve fibers with dystrophic axons containing large
numbers of mitochondria (Fig. 7), and others containing degenerating axons with dark cytoplasm (Fig. 8)
can be found. In contrast, significant numbers of nerve
fibers are probably lost from white matter with age.
Similar to the observation by Lintl and Braak (1983)
and Kemper (1994) drew attention to the fact that in the
cerebral hemispheres of the normal primates the staining of white matter in old brains is paler than in young
Fig. 3. Optic radiation from a 31 year old rhesus monkey. In the middle of the field is a nerve fiber with a large fluid filled balloon
(b) that has pushed the axon (A1 ) to one side of the sheath. On the left is an axon (A2 ) with a thick sheath showing several
circumferential splits. Another nerve fiber in this field has a split sheath (∗) and the axon (A3 ) has electron dense cytoplasm,
which is an indication that the axon is degenerating. Scale bar = 1 µm.
Fig. 4. A longitudinally sectioned nerve fiber in area 46 of prefrontal cortex from a 32 year old rhesus monkey. The sheath of
the nerve fiber has split and bulges out because of the accumulation of dense cytoplasm within it (asterisk). Scale bar = 2 µm.
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Myelin and nerve fibers in aging
brains, and stereological analyses (e.g. Pakkenberg &
Gundersen, 1997; Tang et al., 1997) indicate that there is
a loss of white matter volume from the cerebral hemispheres of humans with age. Tang et al. (1997), for example, estimate that with age there is a 15 to 17% loss
of white matter from the cerebral hemispheres, with a
concomitant 27% reduction in the total length of myelinated nerve fibers. There is also MRI data on humans
(Albert, 1993; Guttman et al., 1998) and on monkeys (Lai
et al., 1995) that concur with this conclusion. However,
there are other studies, such as the one by Andersen
et al. (1999) on the brains of rhesus monkeys, suggesting that gray matter loss exceeds white matter loss. The
reason for these different conclusions drawn from MRI
studies may be the difficulty in knowing exactly where
to place the boundary between white and gray matter
in scans of the cerebral hemispheres.
In an attempt to resolve the issue of whether nerve
fibers are lost with age we have begun to examine welldefined fiber tracts. In the first study we examined the
optic nerves of rhesus monkeys (Sandell & Peters, 2001)
and found that the number of nerve fibers is reduced
from an average of 1.6 × 106 in young optic nerves to as
few as 4 × 105 in one old monkey. But in every old monkey examined some degenerating nerve fibers were evident and the nerve fiber packing density was always
less than in the young monkeys. Consequently, there
is no doubt that nerve fibers are lost from optic nerves
with age, probably due to the degeneration of ganglion
cells. We have now begun to examine the anterior commissure, as another example of a well-defined nerve
fiber bundle, and preliminary data (Sandell & Peters,
unpublished data) indicate that on average there is a
loss of about 50% of nerve fibers from this bundle with
age.
Thus the available stereological data indicate that
there is a loss of myelinated nerve fibers from white
matter with age. Such a loss would result in a diminution of connectivity between components of the central
nervous system and add to the conduction velocity
problems brought about by alterations in the structure
of some myelin sheaths.
Neurologists have also observed changes in white
matter with age. For example, O’Sullivan et al. (2001)
have used diffusion tensor MRI to look for age-related
alterations in white matter. They find that diffusional
anisotropy, which is a marker of white matter tract integrity, is reduced in old subjects and decreases linearly
with age. The white matter disruption is maximal in
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frontal regions and O’Sullivan et al. (2001) consider that
the consequent cortical disconnection is the basis for
the age-related cognitive decline in normal aging. Cerebral white matter lesions have also been associated with
cognitive dysfunction and in a large sample of elderly
subjects De Groot et al. (2000) concluded that periventricular white matter changes have a dominant role in
bringing about cognitive decline, due, perhaps, to interruptions in long connecting tracts in white matter.
The origins of nerve fibers that are lost from, or damaged in, the white matter of the cerebral cortices, are
not known, but it is to be presumed that they originate from some of the projecting pyramidal cells in
the cortex. However, if there is no significant loss of
cortical neurons, then the projecting myelinated axons
must degenerate without loss of the parent cell body. It
is possible that the cortical neurons do not degenerate
because they are sustained by the very extensive local
plexuses that all pyramidal cells generate in the cortex
itself.
Activation of neuroglial cells
While there is evidence for degeneration of myelin
sheaths in cerebral cortex with age, there is little evidence for extensive phagocytosis of myelin. A few
astrocytes in old monkeys have been seen to contain
myelin figures (e.g. Peters & Sethares, 2002) and in addition some of their amorphous inclusions bodies label
with antibodies to myelin basic protein (MBP), which
is one of the main constituents of myelin (Peters &
Sethares, 2003). Microglial cells are usually regarded as
the phagocytes of the central nervous system, and use
of antibodies to HLA-DRm, a MHC class II antigen,
indicates that microglial cells do become activated in
the cerebral hemispheres of old monkeys (Sloane et al.,
1999). However, in cerebral cortex the microglia have no
inclusions in their perikarya with the features of myelin,
and their inclusions do not label with antibodies to
myelin basic protein (MBP). Consequently, astrocytes
appear to be the principal phagocytes of degenerating
myelin in cerebral cortex, and our studies of fiber tracts
suggest that it requires degeneration of entire nerve
fibers to activate microglia to phagocytose degenerating myelin.
Thus in the optic nerve, from which significant numbers of nerve fibers are lost during normal aging
(Sandell & Peters, 2002), both the oligodendrocytes and
the microglial cells become more numerous with age.
Fig. 5. An oligodendrocyte in the visual cortex of a 35 year old rhesus monkey. The oligodendrocyte (O) has dark cytoplasm
that contains dense inclusions (I). Similar inclusions are also present in the swelling along the process (P) extending from this
cell. Scale bar = 2 µm.
Fig. 6. A group of three oligodendrocytes (O) in the visual cortex of a 28 year old rhesus monkey. The cytoplasm of one of the
oligodendrocytes has numerous dense inclusions (I). Scale bar = 2 µm.
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Myelin and nerve fibers in aging
The astrocytes do not increase in number, but they develop abundant filaments and undergo hypertrophy to
fill the space vacated by the degenerating nerve fibers.
However, all three main types of neuroglial cells come
to contain inclusions. The oligodendrocytes have the
dark, sometimes lamellar, inclusions that are common
in these cells throughout the aging brain, and the astrocytes also come to contain their characteristic inclusions. But in those old optic nerves with the most degenerating nerve fibers the microglia become engorged
with debris, which can be recognized as degenerating myelin (Fig. 9). In many ways this parallels the
activation of microglia that occurs when nerve fibers
are damaged and undergo Wallerian degeneration (e.g.,
Kreutzberg et al., 1998).
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sessed, and it is likely that these changes are only two
among many factors that bring about cognitive decline.
For example, although there is no extensive loss of cortical neurons in normal aging, neurons do lose dendritic
branches and spines, and there are alterations in the levels of some neurotransmitters and their receptors. But
as pointed out earlier, studies on the effects of normal
aging on the central nervous system are in their infancy,
and we are nowhere near being able to appreciate all
of the factors that change with age, and which ones
are dominant in bringing about age-related cognitive
decline.
References
ALBERT, M. (1993) Neuropsychological and neurophysio-
Conclusions
Although there is no evidence for a significant loss
of cortical neurons during normal aging on the cerebral hemispheres, there is widespread damage to the
myelin sheaths that ensheath their axons, as evidenced
by structurally altered myelin sheaths observed in electron microscopic preparations. In the cerebral cortex of
monkeys the frequency of the alterations in sheaths correlates significantly with a decline in cognitive status,
and it is suggested that the basis of this correlation is
that breakdown of myelin reduces the rate of conduction of the affected nerve fibers, which in turn alters
the timing in neuronal circuits. In cerebral cortex there
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Fig. 7. A nerve fiber in area 46 of prefrontal cortex of a 27 year old rhesus monkey. The dystrophic axon contains numerous
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Fig. 8. A degenerating nerve fiber in the optic radiation from a 31 year old rhesus monkey. The axon (A) of the nerve fiber is
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